1. Field of the Invention
The invention relates generally to angiogenesis and, more specifically, to compounds and compositions for the treatment of disorders associated with angiogenesis.
2. Background Information
Angiogenesis may be defined as the development of a blood supply to a given area of tissue. The development of a blood supply may be part of normal embryonic development, represent the revascularization of a wound bed, or involve the stimulation of vessel growth by inflammatory or malignant cells. Sometimes angiogenesis is defined as the proliferation of new capillaries from pre-existing blood vessels. New growth of soft tissue requires new vascularization, and the concept of angiogenesis is a key component of tissue growth and in particular, a key point of intervention in pathological tissue growth.
Angiogenesis is a fundamental process necessary for embryonic development, subsequent growth, and tissue repair. Angiogenesis is a prerequisite for the development and differentiation of the vascular tree, as well as for a wide variety of fundamental physiological processes including embryogenesis, somatic growth, tissue and organ repair and regeneration, cyclical growth of the corpus luteum and endometrium, and development and differentiation of the nervous system. In the female reproductive system, angiogenesis occurs in the follicle during its development, in the corpus luteum following ovulation and in the placenta to establish and maintain pregnancy. Angiogenesis additionally occurs as part of the body's repair processes, e.g., in the healing of wounds and fractures.
Nevertheless, angiogenesis is implicated in a number of important human diseases including cancer, diabetic retinopathy, and rheumatoid arthritis. Since the angiogenesis hypothesis was first put forward in 1971, the physiologic and pathological roles of angiogenesis in various biological and disease processes have been subject to extensive scrutiny. The importance of angiogenesis in human diseases such as cancer is well established. Significant progress in anti-angiogenic drug discovery and development has also been made, culminating in the development of angiogenesis inhibitors as drugs for the treatment of cancer and age-related macular degeneration. Angiogenesis inhibitors have been found to be particularly useful when used in conjunction with other chemotherapeutic drugs. Angiogenesis also contributes to the pathogenesis of a number of other diseases, including obesity, psoriasis, Kaposi's sarcoma, diabetic retinopathy, pulmonary hypertension, and arthritis. It is thus not surprising that an estimated 500 million people worldwide may benefit from treatments that modulate angiogenesis.
A number of existing drugs have been found to possess anti-angiogenic effects either serendipitously or by rational prediction. One of the first anti-angiogenic drug candidates to enter clinical trials is TNP-470, a derivative of the anti-amebic drug fumagillin, which was discovered in the late 1980s from a fungal contamination that inhibited endothelial cell culture growth. Other existing drugs such as thalidomide, non-steroidal anti-inflammatory agents and rapamycin also inhibit angiogenesis and have shown promise in clinical trials for the treatment of cancer. Although new uses for several dozen existing drugs such as fumagillin have been found serendipitously or through knowledge of pharmaceutical side effects, a systematic assembly and screening of libraries of existing drugs for novel pharmacological activities did not begin until recently. Consequently, there is a need for new specific targets which can be indicative for angiogenesis inhibition. It is therefore an object of the invention to provide a target for biological screening of compounds for angiogenesis inhibition.
Furthermore, many materials which appear promising in vitro have proven to be relatively ineffective when applied in vivo. Similarly, various of such materials have been found to be unstable, toxic, or otherwise difficult to employ. Consequently, there is a need for methods and materials capable of controlling and inhibiting angiogenesis in a reliable manner. It is therefore an object of the invention to provide compounds and pharmaceutical compositions which exhibit activity as inhibitors of angiogenesis.